Description of Research
The Yang Lab studies the molecular and cellular mechanisms that protect against major diseases, including cancer and neurodegeneration. Our current projects are focused on three areas: 1) apoptosis pathways, 2) the tumor suppressor p53, and 3) the cellular systems that degrade misfolded proteins. Our experimental strategies include molecular and cell biology techniques, biochemical techniques, metabolic analysis, cell culture, genomics, mouse disease models, and human patient samples.

Apoptosis is a physiological process of cell auto-destruction that eliminates unwanted, damaged, or harmful cells. Dysregulation of apoptosis is associated with many diseases such as cancer, neurodegeneration, and immunodeficiency. Apoptosis is executed by the caspase family of cysteine proteases. We previously pioneered a paradigm for the activation of caspases, whereby initiator caspase activation is controlled by oligomerization. We are investigating the regulation of caspase activation in various apoptosis pathways. Paradoxically, some caspases are also involved in cell proliferation. We are studying the proliferative role of caspases to better understand the interplay between cellular life and death processes.

p53 plays a preeminent role in blocking tumor formation and is the single most frequently mutated gene in human tumors. p53 is activated by various tumor-promoting stresses and effectuates a range of anti-proliferative and repair responses. We are investigating the regulation and functions of p53, as well as its structural homologue p73. We previously identified a complex that stabilizes the principal p53 antagonist Mdm2 and are now examining how this complex controls p53 activation. We also revealed a role for p53 family proteins in modulating cellular metabolism, particularly the production of NADPH, the reducing equivalent required for biosynthesis and anti-oxidant defense. We are further studying how these proteins act as both sentinels and regulators for metabolism, coordinating metabolism with cell fate decision, and how these functions may be compromised in tumor cells. We are also investigating other metabolic alterations in tumor cells that enable their survival, proliferation, and metastasis.

Proteins are the most abundant macromolecules in the cell and are critical to virtually all physiological processes. However, proteins are prone to misfolding, and accumulation of misfolded proteins is genetically and pathologically linked to neurodegenerative diseases and cancer. Cells ultimately rely on degradative systems to maintain protein quality. We recently identified a cellular system that selectively degrades misfolded proteins through sequential SUMOylation and ubiquitination, and protects against neurodegeneration. We are further defining the mechanism of this novel protein quality control system, as well as its dysregulation in human diseases.